Our long-term objective is to understand the nature of all gene products involved in the various stages of infection, disease and death of mice caused by Salmonella typhimurium when the pathogen is administered by its normal oral route of entry. We are also interested in understanding how the genes encoding these virulence attributes are regulated in response tothe eukaryotic host. These studies should facilitate understanding infections caused by Salmonella species in other animals, including humans. Specifically we will: 1) evaluate the genetic basis for differential survival of enteric pathogens passing from the oral cavity to the small intestine, 2) investigate the importance of type I pili and mannose-resistant adherence for attachment to and uptake into cells of the gut associated lymphoid tissue, 3) investigate the genetic basis by gene cloning of the differential virulence of strains LT2 versus SR11, particularly in their abilities for colonization and infection of the gut associated lymphoid tissue, 4) examine the role of the 100 kb "cryptic" plasmid in virulence, particularly for its contributions to enhanced survival in macrophages, 5) investigate the role of the LPS core and 0-side chain in virulence by using galE and pmi mutants, 6) isolate and characterize transposon-induced mutants with defects in various stages of infection, and 7) determine how the genes specifying important virulence attributes are regulated in response to the animal host. The studies will make use of the technologies of microbial genetics, molecular biology, biochemistry, immunology and animal science. Experiments will be conducted to preclude infection of workers or inadvertent release of infectious microorganisms.